This invention relates to new RAR selective retinoid agonists, to the use of such retinoic acid receptor agonists, particularly retinoic acid receptor xcex3 (RARxcex3) selective agonists for the treatment of emphysema.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, ranking third and fourth as the leading cause of death in the European Union and North America respectively. COPD is characterized by reduced maximum expiratory flow, which does not change over several months and which persists for 2 or more consecutive years. Patients with the most severe form of COPD generally present with a significant degree of emphysema. Emphysema is defined anatomically by permanent airspace enlargement distal to the terminal bronchioles. It is characterized by gradual loss of lung recoil, alveolar destruction, decreased alveolar surface area and gas exchange, leading to a reduced FEV1. These two features, impaired gas exchange and reduction in expiratory flow, are characteristic physiological abnormalities from which patients with emphysema suffer. The main symptom of patients with severe emphysema is shortness of breath during minimal physical activity.
The most common cause of emphysema is cigarette smoking although other potential environmental toxins may also contribute. These various insulting agents activate destructive processes in the lung including release of active proteases and free radical oxidants in excess of protective mechanisms. The imbalance in protease/anti-protease levels leads to destruction of the elastin matrix, loss of elastic recoil, tissue damage and continuous decline in lung function. Removing the injurious agents (i.e. quit smoking) slows the rate of damage, however, the damaged alveolar structures do not repair and lung function is not regained.
Retinoic acid is a multifunctional modulator of cellular behavior, having the potential to alter both extracellular matrix metabolism and normal epithelial differentiation. In lung, retinoic acid has been shown to modulate various aspects of lung differentiation by interacting with specific retinoic acid receptors (RAR) that are selectively expressed temporally and spatially. Coordinated activation of RARxcex2 and RARxcex3 has been associated with lung branching and alveolization/septation. During alveolar septation, retinoic acid storage granules increase in the fibroblastic mesenchyme surrounding alveolar walls and RARxcex3 expression in the lung peaks. Depletion of these retinyl-ester stores parallels the deposition of new elastin matrix and septation. In support of this concept, (Massaro et al., Am. J. Physiol., 1996, 270, L305-L310) demonstrated that postnatal administration of retinoic acid increases the number of alveoli in rats. Furthermore, the capacity of dexamethasone to prevent the expression of CRBP and RARxcex2 mRNA and subsequent alveolar septation in developing rat lungs was abrogated by all-trans retinoic acid.
Recent studies demonstrated that all-trans retinoic acid can induce formation of new alveoli and return elastic recoil to near normal in animal models of emphysema (D. Massaro et al. Nature Medicine, 1997, 3, 675). However, the mechanism by which this occurs remains unclear.
Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds. Several series of retinoids have been found clinically useful in the treatment of dermatological and oncological diseases. Retinoic acid and its other naturally occurring retinoid analogs (9-cis retinoic acid, all-trans 3,4-didehydro retinoic acid, 4-oxo retinoic acid and retinol) are pleiotropic regulatory compounds that modulate the structure and function of a wide variety of inflammatory, immune and structural cells. They are important regulators of epithelial cell proliferation, differentiation and morphogenesis in lungs. Retinoids exert their biological effects through a series of hormone nuclear receptors that are ligand inducible transcription factors belonging to the steroid/thyroid receptor super family. The retinoid receptors are classified into two families, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), each consisting of three distinct subtypes (xcex1, xcex2, and xcex3). Each subtype of the RAR gene family encodes a variable number of isoforms arising from differential splicing of two primary RNA transcripts. All-trans retinoic acid is the physiological hormone for the retinoic acid receptors and binds with approximately equal affinity to all the three RAR subtypes, but does not bind to the RXR receptors for which 9-cis retinoic acid is the natural ligand.
In many non-pulmonary tissues, retinoids have anti-inflammatory effects, alter the progression of epithelial cell differentiation, and inhibit stromal cell matrix production. These properties have led to the development of topical and systemic retinoid therapeutics for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Other applications include the control of acute promyelocytic leukemia, adeno- and squamous cell carcinoma, and hepatic fibrosis. A limitation in the therapeutic use of retinoids outside of cancer has stemmed from the relative toxicity observed with the naturally occurring retinoids, all-trans retinoic acid and 9-cis retinoic acid. These natural ligands are non-selective and therefore have pleiotropic effects throughout the body, which are often toxic. Recently various retinoids have been described that interact selectively or specifically with the RAR or RXR receptors or with specific subtypes (xcex1, xcex2, xcex3) within a class.
In one aspect, this invention provides new RAR selective retinoid agonists of formula I: 
wherein
the dotted bond is either present and forms a double bond, or is absent;
R1, R2, R3, R4 are independently of each other hydrogen or alkyl;
X is R8R9C less than  for n=1, 2 or 3; or
X is oxygen for n=1;
R8 and R9 are independently of each other hydrogen or alkyl;
R5 is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR10-, alkenyl, alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl, phenyl-alkyl,
R10 is hydrogen or alkyl;
m is 0 when the dotted bond is present; and
m is 1 when the dotted bond is absent; and
A is a residue of formula: 
xe2x80x83or of formula: 
xe2x80x83wherein
Ar is phenyl or a heteroarylic ring;
R6 is hydrogen, halogen, alkoxy or hydroxy;
R7 is hydrogen or alkyl; and
Y xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONR10xe2x80x94, xe2x80x94NR10COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COCHxe2x95x90CHxe2x80x94, xe2x80x94CHOHCHxe2x95x90CHxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94CH2SOxe2x80x94, xe2x80x94CH2SO2xe2x80x94, xe2x80x94CH2NR10xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94SOCH2xe2x80x94, xe2x80x94SO2CH2xe2x80x94 or xe2x80x94NR10CH2xe2x80x94, with the proviso that when Y is xe2x80x94OCOxe2x80x94, xe2x80x94NR10COxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94SOCH2xe2x80x94, xe2x80x94SO2CH2xe2x80x94 or xe2x80x94NR10CH2xe2x80x94, R5 is hydrogen, alkyl,, alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl;
and pharmaceutically active salts of carboxylic acids of formula I.
Activation of RAR has been associated with lung branching ald alveolization. The retinoids according to the invention possess RAR agonist activity. Therefore such compounds would be useful for the treatment of emphysema and related pulmonary diseases. They may also be useful for the therapy and prophylaxis of dermatological disorders which are accompanied by epithelial lesions, e.g. acne and psoriasis, light- and age-damaged skin; as well as for the promotion of wound healing, for example of incised wounds, such as surgical wounds, wounds caused by burns and other wounds caused by cutaneous trauma; and for the therapy and prophylaxis of malignant and premalignant epithelial lesions, tumours and precancerous changes of the mucous membrane in the mouth, tongue, larynx, oesophagus, bladder, cervix and colon.
The term xe2x80x9calkylxe2x80x9d as used herein denotes straight chain or branched alkyl residues containing 1 to 10, preferably 1 to 7 carbon atoms,, such as methyl, ethyl, isobutyl, pentyl, amyl and 3-pentyl, hexyl, heptyl, and the like; the alkyl chain may be substituted by amino, hydroxy, halogen. Such groups are for example hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, aminomethyl, 2-aminoethyl and the like.
As used herein, the term xe2x80x9calkoxyxe2x80x9d refers to a straight or branched chain hydrocarbonoxy group wherein the xe2x80x9calkylxe2x80x9d portion is an alkyl group as defined above. Examples include methoxy, ethoxy, n-propoxy and the like.
As used herein, the term xe2x80x9calkoxy-alkyl-xe2x80x9d refers to a dialkylether residue such as methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, methoxyethoxymethyl and the like.
As used herein, the term xe2x80x9calkylthioxe2x80x9d refers to a straight or branched chain hydrocarbonthio group wherein the xe2x80x9calkylxe2x80x9d portion is an alkyl group as defined above. Examples include methylthio, ethylthio, propylthio, and the like.
As used herein the term xe2x80x9calkenylxe2x80x9d refers to a straight or branched hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond, e.g. allyl, vinyl etc.
As used herein, the term xe2x80x9calkenyloxyxe2x80x9d refers to a straight or branched chain hydrocarbonoxy group wherein the xe2x80x9calkenylxe2x80x9d portion is an alkenyl group as defined above. Examples include allyloxy, 3-butenyloxy and the like.
As used herein the term xe2x80x9calkynylxe2x80x9d refers to a straight or branched hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one triple bond.
The term xe2x80x9ccycloalkyl-alkylxe2x80x9d as used herein refers to alkyl groups as defined above bearing a cycloalkyl group having 3 to 7 carbon atoms as for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl and the like.
As used herein the term xe2x80x9cphenyl-alkylxe2x80x9d refers to a alkyl group as defined above having a phenyl group attached to the terminal C-atom as benzyl, phenethyl, phenylpropyl and the like, the phenyl group may unsubstituted or substituted by alkyl or alkoxy.
The term xe2x80x9cheteroarylic ringxe2x80x9d as used herein refers to a 5 or 6-membered heteroaryl ring containing at least one hetero atom selected from oxygen, sulfur, and nitrogen for example to pyridinyl, furanyl or thiophenyl. In formulae I, I-1 and IA-IH, xe2x80x9cArxe2x80x9d surrounded by hexagon can indicate a heteroarylic ring having at least three ring carbon atoms, in which case the heteroarylic ring is bonded to each of Y, R6 and xe2x80x94C(O)OR7 via a different ring carbon atom. Alternatively Ar surrounded by hexagon can indicate phenyl, in which case Y and xe2x80x94C(O)OR7 are para to each other.
The groups Y are shown in their orientation in the compound of formula I. By way of illustration when Y is xe2x80x94CONR10xe2x80x94, the nitrogen is bonded directly to the group Ar.
The compounds of formula I, wherein R7 is hydrogen, form salts with pharmaceutically acceptable bases such as alkali salts, e.g. Na- and K-salts, and ammonium or substituted ammonium salts such as trimethylammonium salts which are within the scope of this invention.
When n is 2 or 3 in the formulae given in this application, each occurrence of R8 can be the same or different and each occurrence of R9 can be the same or different. It is preferred that all occurrences of R8 are the same as the others and that all occurrences of R9 are the same as the others. When n is 1, 2 or 3, it is most preferred for each R8 and each R9 to be hydrogen.
Preferred compounds of formula I are the compounds of formula: 
wherein
the dotted bond is present and forms a double bond, or is absent;
R1, R2, R3, R4 are independently of each other hydrogen or alkyl;
X is R8R9C less than  for n=1, 2 or 3; or
X is oxygen for n=1;
R5 is hydrogen, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl or phenylalkyl;
m is 0 when the dotted bond is present; or
m is 1 when the dotted bond is absent;
Ar is phenyl or heteroarylic ring;
R6 is hydrogen, halogen, alkoxy or hydroxy;
R7 is hydrogen or alkyl;
R8 and R9 are independently of each other hydrogen or alkyl; and
Y xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94COCHxe2x95x90CHxe2x80x94, xe2x80x94CHOHCHxe2x95x90CHxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94 or xe2x80x94CH2NHxe2x80x94; with the proviso that when Y is xe2x80x94OCOxe2x80x94 or xe2x80x94NHCOxe2x80x94, R5 is hydrogen, alkyl, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or phenylalkyl;
and pharmaceutically active salts of carboxylic acids of formula I-1.
Especially preferred are the compounds of formulas: 
wherein the symbols are as defined above, X2 is oxygen or xe2x80x94NHxe2x80x94 and Z is oxygen, sulfur or xe2x80x94NHxe2x80x94;
and pharmaceutically active salts of carboxylic acids of formulae IA-IH.
The double bond in compounds of formulae IB, IE and IF may form an E/Z mixture or be E or Z configurated, preferably E configurated. The zigzag line in these formulae above indicates that the configuration can be E or Z.
Preferred compounds are those wherein X is R8R9C less than  and n is an integer 1 or 2.
Especially preferred are compounds of formula IA wherein X2 is oxygen and n is 2, for example





2-propyl-4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid 4-carboxy-phenyl ester
2-butyl-4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid 4-carboxy-phenyl ester
2-hexyl-4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid 4-carboxy-phenyl ester
2-phenethyl-4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid 4-carboxy-phenyl ester.
Further preferred are compounds of formula IA wherein Ar is pyridine, i.e.
6-[(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbonyl)-amino]-nicotinic acid 
Further preferred are compounds of formula IA wherein n is 1 and X is R8R9C less than :
4,4,6,6-tetramethyl-2-pentyl-1,2,3,4,5,6-hexahydro-pentalene-2-carboxylic acid 4-carboxy-phenyl ester;
and compounds wherein n is 1 and X is oxygen
1,1,3,3-tetramethyl-5-pentyl-3,4,5,6-tetrahydro-1H-cyclopenta[c]furan-5-carboxylic acid 4-carboxy-phenyl ester.
A further group of preferred compounds are compounds
a) of formula IB:
4-[2-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-yl)-vinyl]-benzoic acid; 
b) of formula IC:
4-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-ylethynyl)-benzoic acid 
c) of formula ID, wherein Z is oxygen:
4-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-ylmethoxy)-benzoic acid;
xe2x80x83of formula ID, wherein Z is sulfur:
4-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-ylmethylsulfanyl)-benzoic acid; and
xe2x80x83of formula ID, wherein Z is xe2x80x94NHxe2x80x94:
4-[-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-ylmethyl)-amino]-benzoic acid;
d) of formula IE
4-[3-oxo-3-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-yl)-propenyl]-benzoic acid; and
e) of formula IF
4-[3-hydroxy-3-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-propenyl]-benzoic acid;
Further preferred compounds of formula I are the compounds of formula 
wherein
the dotted bond is present and forms a double bond, or is absent;
R1, R2, R3, R4 are independently of each other hydrogen or alkyl;
X is R8R9C less than  for n=1, 2 or 3; or
X is oxygen for n=1;
R8 and R9 are independently of each other hydrogen or alkyl;
R5 is hydrogen, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl, phenyl-alkyl;
m is 0 when the dotted bond is present; or
m is 1 when the dotted bond is absent; and
R7 is hydrogen or alkyl;
and pharmaceutically active salts of carboxylic acids of formula I-2.
Especially preferred compounds of formula I-2 are
(2E,4E,6E)-3-methyl-7-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-hepta-2,4,6-trienoic acid; 
(2Z,4E,6E)-3-methyl-7-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-hepta-2,4,6-trienoic acid. 
The compounds according to the invention can be prepared in a manner known in the art. In particular compounds of formula IA, wherein X2 is oxygen or xe2x80x94NHxe2x80x94 may for example be prepared according to scheme 1: 
wherein
X, n, m and Ar are defined as above and
R5 is hydrogen, alkyl, alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl, phenyl-alkyl;
X1 is a halogen, preferably bromide or iodide;
X2xe2x80x2 is xe2x80x94OH or NH2;
X2 is oxygen or xe2x80x94NHxe2x80x94; and
R10 is R7 or a carboxylic acid protecting group, preferably an allylic group.
LDA is lithium diisopropylamide; and
DCC/DMAP is dicyclohexylcarbodiimide/dimethylamino pyridine.
The acid 1, wherein the dotted line is absent and thus m is 1, can be alkylated with a suitable alkylhalogenide preferably an alkylbromide or an alkyliodide, or with an alkyl sulfonate, e.g. tosylate or mesylate, using a strong base, e.g. lithium diisopropylamide or potassium tert.-butylate, to give the alkylated acid 2, which is condensed with a hydroxy- or aminoaryl carboxylic acid ester 3 to give compound 4. In the alternative the alkylation step is omitted for compounds of formula IA, wherein the dotted bond is present and m is thus 0. As condensation agent dicyclohexylcarbodiimide/4-dimethylaminopyridine can be used. Alternatively the acid 2 (or 1, respectively) can be transformed into the acid chloride (thionyl chloride, oxalyl chloride) and then reacted with compounds 3 and in the presence of a base (pyridine, triethylamine). R10 in compound 3 can be R7 when X2xe2x80x2 is NH2 or must be a carboxylic acid protecting group like allyl-, xcex2-trimethylsilylethyl-, tert.-butyl- or 4-(trimethylsilyl)-2-buten-1-yl- or benzyl, when X2xe2x80x2 is xe2x80x94OH. The carboxylic acid protecting group can be removed in the last step without cleavage of the internal amide or ester bond with such agents as Pd(0)/morpholine or Pd(0)/Bu3SnH for the allyl group, Bu4NF for the xcex2-trimethylsilylethyl group, formic acid for the tert.-butyl group or Pd(0) for the 4-(trimethylsilyl)-2-buten-1-yl group or catalytic hydrogenation for the benzyl group.
The acid 1, wherein the dotted line is absent and thus m is 1, used as starting material can be prepared in analogy to the examples given in EP 116 277 and EP 115 274. The acid 1, wherein the dotted line is present and forms a double bond are prepared as depicted in scheme 1a below. Starting from the ester of formula 1a which is transformed to the corresponding unsaturated compound 1b as depicted in scheme 1a: 
wherein the symbols are as defined above, R7xe2x80x2 is alkyl, LDA is lithium diisopropylamide and Ph is phenyl.
Compounds of formula I, wherein Y is xe2x80x94CHxe2x95x90CHxe2x80x94, i.e. compounds of formula IB may be prepared according to scheme 2: 
wherein the symbols are as defined above and Et signifies ethyl.
The acid 2 can be reduced to the alcohol 5 (e.g. with LiAlH4, or a borane complex), oxidized to the aldehyde 6 by a Swern or a Dess-Martin oxidation or with pyridinium chlorochromate and then condensed in a Wittig-Horner reaction with a suitable phosphonate 7 using a strong base like NaH or lithium-bis-(trimethylsilyl)-amide (LiHMDS) to give the olefinic compounds of formula IB wherein R7 is different from hydrogen and which can be hydrolyzed if desired to a compound of formula IB wherein R7 is hydrogen. The double bond may be in a E/Z mixture, or preferably in the E configuration. The Wittig-Horner reaction is highly trans selective and Scheme 2 illustrates the synthesis of the trans isomer. The corresponding cis isomer may be prepared in accordance with Scheme 3, followed by Lindlar reduction of the triple bond.
Compounds of formula I wherein Y is an acetylenic group (xe2x80x94Cxe2x89xa1Cxe2x80x94), namely compounds of formula IC can be prepared according to scheme 3: 
wherein the symbols are as defined above and X3 is halogen, preferably bromine or iodine.
The aldehyde 6 can be transformed into the acetylenic derivative 9 according to the method of Corey and Fuchs by reaction with P(C6H5)3/CBr4 and subsequently with butyllithium. The lithiated product is then coupled with a bromo or iodo substituted aromatic ester 8 in a Pd(0) catalyzed reaction to give a compound of formula IC wherein R7 is different from hydrogen and which can be hydrolyzed to the product wherein R7 is hydrogen if desired.
Compounds of formula I wherein Y is xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94 or xe2x80x94CH2NR10xe2x80x94, i.e. compounds of formula ID, wherein Z is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94, can be synthesized according to Scheme 4 by using an alcohol 5 as starting material. 
wherein the symbols are as defined above and X2xe2x80x3 is xe2x80x94OH, xe2x80x94SH or xe2x80x94NH2.
The hydroxy group of the alcohol 5 can be transformed to the halogenated derivative 10 with PX33 or CX43/(C6H5)3P, wherein X3 is a halogenide preferably a chloride or bromide, or to a sulfonate using mesyl chloride or tosyl chloride followed by reaction with compound 11 to give the product of formula ID, which may be hydrolyzed to the product of formula ID wherein R7 is hydrogen.
Compounds of formula ID, wherein Z is sulfur can be oxidized to the sulfoxide or the sulfone with peroxides. An alternative method for the synthesis of compounds of formula ID wherein Z is oxygen or sulfur is according to Mitsunobu by reacting the alcohol 5 with compound 11 wherein X2xe2x80x3 is OH or SH.
Compounds of formula I, wherein Y is xe2x80x94COCHxe2x95x90CHxe2x80x94, i.e. compounds of formula IE can be synthesized according to scheme 5. 
wherein the symbols are as defined above.
The ketone 12 can be alkylated at the higher substituted position by using sodium hydride (NaH), potassium hydride (KH) or potassium tert.-butylate as a base to give compounds 13 wherein the dotted bond is absent and m is 1. Aldol condensation of compounds 12 or 13, respectively, with formyl compound 14 in the presence of catalytic amounts of sodium hydroxyde (NaOH), piperidine, piperidinium acetate or piperidinium tosylate yields compounds of formula IE wherein R7 is different from hydrogen which can be transformed into the final product IE wherein R7 is hydrogen by hydrolysis of the ester group.
Compound of formula I, wherein Y is xe2x80x94CHOHCHxe2x95x90CHxe2x80x94, i.e. compounds of formula IF can be prepared according to scheme 6 by reduction of a compound of formula IE with for example NaBH4 or with NaBH4/CeCl3. 
wherein the symbols are as defined above.
Compounds of formula IF wherein R7 is different from hydrogen can be transformed into the product IF wherein R7 is hydrogen by hydrolysis.
The compounds of formula I, wherein Y is xe2x80x94NR10COxe2x80x94, i.e. compounds of formula IG can be prepared according to scheme 7. Various methods are known for the transformation of acid 2 into amine 15 (Hofmann, Lossen, Curtius or Schmidt-rearrangement) 
wherein the symbols are as defined above.
The amine 15 for example can be reacted with a terephthalic acid chloride derivative or a suitable acid chloride 16 in presence of pyridine or triethyl amine to give the amide of formula IG wherein R7 is different from hydrogen. Hydrolysis of the ester group yields the product of formula IG wherein R7 is hydrogen.
In the alternative the internal amide bond can also be formed by reaction of the amine 15 with terephthalic acid half ester and dicyclohexylcarbodiimide.
Compounds of formula I, wherein Y is xe2x80x94OCOxe2x80x94, i.e. compounds of formula IH can be synthesized according to scheme 8.
Compound 12 can be oxidized according to Baeyer-Villiger with a peroxyacid to give the hydroxy compound 17. Esterification is performed using known methods as for example by reaction of an acid chloride 16 and a base. 
wherein the symbols are as defined above.
Compounds of formula I-2 can be prepared according to the method depicted in Scheme 9: 
wherein the symbols are as defined above.
The aldehyde 6 is reacted with the phosphonate 18 in a Wittig-Horner reaction in presence of a strong base as for example sodium hydride or lithium-bis-(trimethylsilyl)-amide (LiHMDS) in an inert solvent as for example THF to the ester of formula I-2, wherein R7 is alkyl. This ester may the subsequently be hydrolyzed to the compound of formula I-2, wherein R7 is hydrogen.
Compounds of formula I, wherein R5 is alkoxy, alkylthio and alkyl-NR10xe2x80x94 and Y is different from xe2x80x94OCOxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94SOCH2xe2x80x94, xe2x80x94SO2CH2xe2x80x94 or xe2x80x94NR10CH2xe2x80x94 can be prepared by known methods for example they may be prepared according to the methods depicted in scheme 10. 
wherein the symbols are as defined above.
The ester 1a can be transformed into the ester enolate 1b in presence of a strong, non-nucleophilic base like lithium diisopropylamide, this enolate can then be reacted with:
a) MoO5-complex to give the corresponding xcex1-hydroxy compound which can then be alkylated with an alkylhalogenide (R5X1) to form compound 19 which is then transformed according to one of the reaction schemes above into the desired compound of formula I;
b) a suitable disulfide alkyl-Sxe2x80x94S-alkyl to give the corresponding xcex1-thioester 20;
c) a [NH2⊕]-synthon (for a review of such synthons see G. Boche in Houben-Weyl, Methods of Organic Chemistry, Vol. E21e, p.5133 (1995) or D. Enders et al. in Tetrahedron 1998, 54, 10069).
Compounds of formula IA, wherein Y is xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94SOCH2xe2x80x94, xe2x80x94SO2CH2xe2x80x94 or xe2x80x94NR10CH2xe2x80x94 and R5 is alkyl, alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl, phenyl-alkyl, can be prepared according to the method depicted in scheme 11: 
wherein the symbols are as defined above.
The acid 22, synthesis described in example 11, can be transformed in a Curtius reaction into the corresponding ketone 23 which will react with Lawesson reagent to the thioketone 24. Addition of a Grignard reagent will lead to compounds 25 and 26, respectively. Alkylation of compounds 15, 25 or 26 with bromomethyl derivative 27 will give the desired products of formula IA, wherein Y is xe2x80x94NHCHxe2x80x94, xe2x80x94OCH2xe2x80x94 or xe2x80x94SCH2xe2x80x94.
In another aspect, this invention is concerned with the use of RAR selective agonist with systemic administration being a preferred mode of delivery for treating emphysema and associated pulmonary diseases. It is thus concerned with a method for treating emphysema and associated pulmonary diseases by treatment of a mammal with a RAR selective agonist with systemic administration being a preferred mode of delivery.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating or preventing a disease, is sufficient to effect such treatment or prevention for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The RARxcex3 agonist selectivity of a compound can be determined by routine ligand binding assays known to one of skill in the art such as described in C. Apfel et al. Proc. Nat. Sci. Acad. (USA), 89:7129-7133 (1992); M. Teng et al., J. Med. Chem., 40:2445-2451 (1997); and PCT Publication WO 96/30009.
The uses of RAR agonists disclosed herein may be used for promoting the repair of damaged alveoli and septation of new alveoli, particularly for the treatment emphysema. Treatment with RAR agonists, particularly, RARxcex3 selective agonists is useful to promote repair of alveolar matrix and septation. As such, the methods disclosed herein are useful for treating diseases such as emphysema.
Typically, the dosage will range between about 0.01 and 1.0 mg/kg body weight per day, preferably from about 0.05 to about 0.5 mg/kg body weight per day.
In particular dosage of a RAR selective agonist required to treat lung emphysema will depend on the severity of the condition. This dosage may be delivered in a conventional pharmaceutical composition by a single administration, by multiple applications, or via controlled release, as needed to achieve the most effective results. Dosing will continue for as long as is medically indicated, which depending on the severity of the disease may range from a few weeks to several months.
Typically, a pharmaceutically acceptable composition, such as a salt, of the RAR agonist of formula I in a pharmaceutically acceptable carrier or diluent is administered. In the context of the present invention, pharmaceutically acceptable salts include any chemically suitable salt known in the art of retinoid agonists as applicable for administration to human patients. Examples of conventional salts known in the art include the alkali metal salts such as sodium and potassium salts, the alkaline earth metal salts such as calcium and magnesium salts, and ammonium and alkyl ammonium salts.
Representative delivery regimens include oral, parenteral (including subcutaneous, intramuscular and intravenous), rectal, buccal (including sublingual), transdermal, pulmonary and intranasal. One method of pulmonary administration involves aerosolization of an aqueous solution of an RAR agonist. Aerosolized compositions may include the compound packaged in reverse micelles or liposomes. Typical pulmonary and respiratory delivery systems are described in U.S. Pat. Nos. 5,607,915, 5,238,683, 5,292,499, and 5,364,615.
The treatment methods of this invention also include systemic administration of RAR agonists in simultaneous or sequential combination with a further active ingredient.
RAR agonists will typically be administered as pharmaceutical compositions in admixture with a pharmaceutically acceptable, non toxic carrier. As mentioned above, such compositions may be prepared for parenteral (subcutaneous, intramuscular or intravenous) administration, particularly in the form of liquid solutions or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; for intranasal administration, particularly in the form of powders, nasal drops or aerosols; and for rectal or transdermal administration. Any conventional carrier material can be employed. The carrier material can be any organic or inorganic carrier material, such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, polyalkylene glycols, petroleum jelly and the like.
Liquid formulations for parenteral administration may contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. They may employ slightly acidic buffers in pH ranges of about 4 to about 6. Suitable buffers include acetate, ascorbate and citrate at concentrations ranging from about 5 mM to about 50 mM. For oral administration, the formulation can be enhanced by the addition of bile salts or acylcarnitines.
Formulations for nasal administration may be solid and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered spray. Particular nasal formulations include dry powders suitable for conventional dry powder inhalers (DPI""s), liquid solutions or suspensions suitable for nebulization and propellant formulations suitable for use in metered dose inhalers (MDI""s). For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
When formulated for nasal administration, the absorption across the nasal mucous membrane may be enhanced by surfactant acids, such as for example, glycocholic acid, cholic acid, taurocholic acid, ethocholic acid, deoxycholic acid, chenodeoxycholic acid, dehydrocholic acid, glycodeoxycholic acid, cyclodextrins and the like in an amount in the range between about 0.2 and 15 weight percent, preferably between about 0.5 and 4 weight percent, most preferably about 2 weight percent.
Solid forms for oral administration include tablets, hard and soft gelatin capsules, pills, sachets, powders, granules and the like. Each tablet, pill or sachet may contain from about 1 to about 50 mg, preferably from 5 to about 10 mg of RAR agonist. Preferred solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. SEG capsules are of particular interest because they provide distinct advantages over the other two forms (see Seager, H., xe2x80x9cSoft gelatin capsules: a solution to many tableting problemsxe2x80x9d; Pharmaceutical Technology, 9, (1985). Some of the advantages of using SEG capsules are: a) dose-content uniformity is optimized in SEG capsules because the drug is dissolved or dispersed in a liquid that can be dosed into the capsules accurately b) drugs formulated as SEG capsules show good bioavailability because the drug is dissolved, solubilized or dispersed in an aqueous-miscible or oily liquid and therefore when released in the body the solutions dissolve or are emulsified to produce drug dispersions of high surface area and c) degradation of drugs that are sensitive to oxidation during long-term storage is prevented because the dry shell.
Delivery of the compounds of the present invention to the subject over prolonged periods of time, for example, for periods of one week to one year, may be accomplished by a single administration of a controlled release system containing sufficient active ingredient for the desired release period. Various controlled release systems, such as monolithic or reservoir type microcapsules, depot implants, osmotic pumps, vesicles, micelles, liposomes, transdermal patches, iontophoretic devices and alternative injectable dosage forms may be utilized for this purpose. Localization at the site to which delivery of the active ingredient is desired is an additional feature of some controlled release devices, which may prove beneficial in the treatment of certain disorders.
The following are representative pharmaceutical formulations for using RAR selective agonists as described herein for promoting elastin mediated matrix repair and alveolar septation.
Tablet Formulation
The following ingredients are mixed intimately and pressed into single scored tablets.
Capsule Formulation
The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Suspension Formulation
The following ingredients are mixed to form a suspension for oral administration.
Injectable Formulation
The following ingredients are mixed to form an injectable formulation.
Nasal Formulation
The following ingredients are mixed to form a suspension for nasal administration.